tbuckley/cabot-search huggingface dataset:
Abstract IA013: Age-related changes in pancreatic fibroblasts drive pancreatic cancer growth and progression
Authors: Daniel Zabransky, Elizabeth Jaffee, Ashani Weeraratna
Journal: Cancer Research (2023)

Abstract Aging is an independent risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). However, the ways in which aging alters cell populations that will ultimately comprise the PDAC tumor microenvironment (TME) are incompletely understood. PDAC tumors are highly desmoplastic, and fibroblasts alter the behavior of pancreatic cancer cells and impact treatment responses. Here, we show that normal pancreatic fibroblasts acquire tumor-promoting properties during aging using both in vitro and in vivo models. To determine if PDAC tumors may be influenced by an aged microenvironment, we performed orthotopic KPC cell injections into the pancreata of aged (&amp;gt;52-week-old) and young (6-8-week-old) syngeneic C57Bl/6J mice. Aged mice have significantly larger tumors, increased incidence of liver metastases, and decreased survival compared to young mice. We next queried whether aged pancreatic fibroblasts contribute to this increase in tumor growth. We generated a panel of aged (donors &amp;gt;55 years old) and young (donors &amp;lt;35 years old) normal human pancreatic fibroblasts to determine the effects of healthy aging fibroblasts on PDAC cell behavior. Conditioned media from aged human pancreatic fibroblasts significantly increases the proliferation of PDAC cells, suggesting that secreted factors produced by aged fibroblasts enhance cancer cell growth. Next, we evaluated changes in the invasiveness of PDAC cells in a 3D co-culture system with either aged or young pancreatic fibroblasts. PDAC spheroids containing cancer cells and aged fibroblasts exhibit a significant increase in invasiveness compared to those containing young fibroblasts. Aged (&amp;gt;52-week-old) compared to young (6-8-week-old) mouse pancreatic fibroblasts also increase the proliferation and invasiveness of KPC cells in vitro, providing evidence that aged fibroblasts may contribute to the phenotypes observed in vivo experiments using aged mouse models. In conclusion, we show that aged, non-cancer-associated pancreatic fibroblasts have the potential to promote growth, migration, and invasiveness in multiple models of pancreatic ductal adenocarcinoma. We hypothesize that factors secreted by pancreatic fibroblast change during aging and that this aged secretome may serve to establish a tumor-promoting niche for pancreatic cancer cells. Citation Format: Daniel Zabransky, Elizabeth Jaffee, Ashani Weeraratna. Age-related changes in pancreatic fibroblasts drive pancreatic cancer growth and progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA013.
Abstract IA011: Mutations in normal cell
Authors: Mike Stratton
Journal: Cancer Research (2023)

Abstract Mutations in DNA/RNA cause the phenotypic variation upon which natural selection acts during evolution. Mutations arise and are transmitted between generations of organisms and between generations of cells in the somatic tissues of multicellular organisms. However, our knowledge of the biological processes that generate mutations and the rates at which they occur in different cell types has been rudimentary until recently. Cancer is a recognized outcome of somatic mutations. However, we have limited understanding of the wider consequences of somatic mutations. I will review our current understanding of the landscape of somatic mutations in normal cells, its causes and its consequences. Citation Format: Mike Stratton. Mutations in normal cell [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA011.
Abstract PR009: Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome
Authors: Christopher J. Minteer, Kyra Thrush, Peter Niimi, Joel Rozowsky, Jason Liu, Mor Frank, Thomas McCabe, Erin Hofstatter, Mariya Rozenblit, Lajos Pusztai, Kenneth Beckman, Mark Gerstein, Morgan E. Levine
Journal: Cancer Research (2023)

Abstract Aging is the leading risk factor for cancer. While some have proposed that the age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. Here, we show that both aging and cancer share a common epigenetic replication signature, which we modeled from DNA methylation data in extensively passaged immortalized human cells in vitro and tested on clinical tissues. This epigenetic signature of replication – termed CellDRIFT – increased with age across multiple tissues, distinguished tumor from normal tissue, and was escalated in normal breast tissue from cancer patients. Additionally, within-person tissue differences were correlated with both predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Overall, our findings suggest that age-related replication drives epigenetic changes in cells, potentially pushing them towards a more tumorigenic state. Citation Format: Christopher J. Minteer, Kyra Thrush, Peter Niimi, Joel Rozowsky, Jason Liu, Mor Frank, Thomas McCabe, Erin Hofstatter, Mariya Rozenblit, Lajos Pusztai, Kenneth Beckman, Mark Gerstein, Morgan E. Levine. Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR009.
Abstract B026: SIWA318H, a novel advanced glycation end product (AGE) specific antibody, targets cancer and senescent cells in the tumor microenvironment and exhibits potent antitumor activity in a humanized mouse model for pancreatic cancer. [R]
Authors: Gabriela Rossi, Lewis Gruber, Misty Gruber, Haiyong Han
Journal: Cancer Research (2023)

Abstract The aging-related and cancer cell derived oxidatively stressed tumor microenvironment drives cell senescence. Senescent cells (SCs), in turn, promote immune suppression, tumor progression, and metastasis. Hence, targeting SCs presents an attractive approach for cancer therapy. SIWA318H is a monoclonal antibody that selectively targets an advanced glycation end product biomarker on the surface of dysfunctional cells exhibiting both (a) aerobic glycolysis and (b) oxidative stress. The SIWA318H biomarker is associated with cancer cells, SCs, oxidatively damaged cells, and infected cells. SIWA318H has been shown to bind to an ADCC inducing human IgG FcγR3 receptor as a mechanism of action. SIWA318H exhibits strong binding to pancreatic cancer patient derived xenograft tumors as demonstrated by immunohistochemistry. In an in vivo study using a humanized mouse xenograft model for pancreatic cancer, we showed that treatment with SIWA318H (both high and low dose groups) statistically significantly reduced tumor growth compared to the isotype antibody control group (P &amp;lt; 0.0001). In addition, there was a significantly higher number of mice had complete remission in the treated groups compared to the isotype control group: 37.5% in high dose group (P = 0.0325) and 43.8% in low dose group (P = 0.0143). Moreover, mice treated with 318H had a median overall survival of &amp;gt; 45 days compared to 26 days for the isotype control mice. There was no difference in animal body weight between the SIWA318H-treated mice and the isotype control mice. Immunohistochemical analysis of tumor tissues taken from the in vivo study showed that SIWA318H treatment significantly reduced (a) tumor fibrosis as measured by the area of αSMA+ staining and (b) the number of senescent cells in the tumor stroma as measured by the number of p16INK4a positive cells in αSMA+ areas. In summary, our results demonstrate that SIWA318H is a novel senolytic antibody that exhibits potent preclinical antitumor activity against pancreatic cancer. SWA318H is currently under development for a first in human clinical trial. Citation Format: Gabriela Rossi, Lewis Gruber, Misty Gruber, Haiyong Han. SIWA318H, a novel advanced glycation end product (AGE) specific antibody, targets cancer and senescent cells in the tumor microenvironment and exhibits potent antitumor activity in a humanized mouse model for pancreatic cancer. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B026.
Abstract B004: Sugar Intake and premature aging in adult survivors of childhood cancer in the St. Jude Lifetime (SJLIFE) Cohort
Authors: Tuo Lan, Mei Wang, AnnaLynn M. Williams, Matthew J. Ehrhardt, Emily R. Finch, Jennifer Q. Lanctot, Shu Jiang, Kevin R. Krull, Gregory T. Armstrong, Melissa M. Hudson, Graham A. Colditz, Leslie Robison, Kirsten K. Ness, Yikyung Park
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR014) of the Conference Proceedings. Citation Format: Tuo Lan, Mei Wang, AnnaLynn M. Williams, Matthew J. Ehrhardt, Emily R. Finch, Jennifer Q. Lanctot, Shu Jiang, Kevin R. Krull, Gregory T. Armstrong, Melissa M. Hudson, Graham A. Colditz, Leslie Robison, Kirsten K. Ness, Yikyung Park. Sugar Intake and premature aging in adult survivors of childhood cancer in the St. Jude Lifetime (SJLIFE) Cohort [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B004.
Abstract A005: The aged tumor microenvironment influences tolerance to targeted therapy via NR2F1 overexpression in BRAF-mutant melanoma
Authors: Manoela Tiago, Timothy J. Purwin, Mitchell E. Fane, Yash Chhabra, Jessica L. F. Teh, Rama Kadamb, Weijia Cai, Inna Chervoneva, Sheera Rosenbaum, Vivian Chua, Nir Hacohen, Michael A. Davies, Jessie Villanieva, Ashani T. Weeraratna, Claudia Capparelli, Julio A. Aguirre-Ghiso, Andrew E. Aplin
Journal: Cancer Research (2023)

Abstract Despite the clinical success of targeted inhibitors, tumor responses to these agents are transient, and drug-tolerant residual cells seed resistance. Understanding the role of tumor-intrinsic mechanisms and effects of the tumor microenvironment in mediating drug tolerance will guide and optimize targeted therapies. Given similarities between drug tolerance and cellular dormancy, we studied the role of nuclear receptor subfamily 2 group F member 1 (NR2F1) in response to targeted therapy. We used BRAF-mutant cutaneous melanoma models treated with BRAF and MEK inhibitors (BRAFi + MEKi) since patients treated with this combination typically develop resistance. The aged tumor microenvironment has been shown to increase therapy resistance, and we find that melanoma cells in aged mice express higher levels of NR2F1 than when the same cells are injected into young animals. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased expression of NR2F1 post-treatment. Similarly, NR2F1 was highly expressed in minimal residual disease collected on BRAFi + MEKi treatment in patient- and xenograft-derived tumors. High expression of NR2F1 promotes tumor survival and invasion in the presence of BRAFi + MEKi in vitro leading to tolerance to BRAFi + MEKi efficacy in vivo. Depletion of NR2F1 in YUMM1.7 allografts grown in aged mice improved response to the combination therapy. Altogether, our findings suggest that NR2F1 promotes drug tolerance leading to minimal residual disease in melanoma and that NR2F1-high cells may be targeted with CDK4/6 inhibitors to improve targeted therapy outcomes in melanoma patients. Citation Format: Manoela Tiago, Timothy J. Purwin, Mitchell E. Fane, Yash Chhabra, Jessica L. F. Teh, Rama Kadamb, Weijia Cai, Inna Chervoneva, Sheera Rosenbaum, Vivian Chua, Nir Hacohen, Michael A. Davies, Jessie Villanieva, Ashani T. Weeraratna, Claudia Capparelli, Julio A. Aguirre-Ghiso, Andrew E. Aplin. The aged tumor microenvironment influences tolerance to targeted therapy via NR2F1 overexpression in BRAF-mutant melanoma [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A005.
Association between BMI and vitiligo distribution: an observational cohort study
Authors: Ross O’Hagan, Samir Kamat, Shira Wieder, Marcel Perl, Nanette Silverberg
Journal: British Journal of Dermatology (2023)

Abstract Vitiligo is an inflammatory skin condition affecting 0·5–2% of people. Previous studies have found that vitiligo does not appear to have an association with an increased body mass index (BMI) nor is BMI a risk factor for vitiligo. However, to the best of our knowledge, the relationship between a patient being over or underweight and the presentation of vitiligo has not been explored. Here, we aim to explore the relationship between BMI classifications and vitiligo distribution. A total of 1685 consecutive patients with vitiligo were recruited as part of an ongoing survey study. Patients self-identified their sex, age, race and regions of vitiligo distribution. Patients reported their height and weight, which was then used to generate BMI values, which were then grouped into classifications. The BMI classifications were underweight for patients with a BMI &amp;gt;18·5, normal for patients with a BMI equal to 18·5 or larger but &amp;lt;30 and overweight for patients with a BMI equal to or over 30. Analysis was performed with R (version 1·4). The cohort (n = 1685) had a median age of 42 years, was predominantly female (72%) and was predominantly white (64%). The patients were divided into three weight classes: 1270 normal weight, 344 overweight and 71 underweight. Vitiligo presentation was more likely for overweight individuals in the chest (P = 0·007), stomach (P &amp;lt; 0·001), underarms (P = 0·005), arms (P = 0·007), elbows (P = 0·031), wrists (P = 0·040), hands (P = 0·003), fingers (P = 0·004), buttocks (P = 0·002), ankles (P = 0·033), feet (P &amp;lt; 0·001) and toes (P = 0·022). Vitiligo presentation does not seem to have a relationship with one’s BMI classification in the distribution of the eyelids, lips, mouth, back, hips, genitals, legs and knees. Our preliminary analysis supports that there is a relationship between a patient’s body mass classification and the distribution of vitiligo. Vitiligo presentation seems to be more likely for overweight individuals in the chest, stomach, underarms, arms, elbows, wrists, hands, fingers, buttocks, ankles, feet and toes. Vitiligo presentation does not seem to have a relationship with one’s BMI classification in the distribution of the eyelids, lips, mouth, back, hips, genitals, legs and knees. The effect of weight-induced friction and metabolic syndrome on vitiligo disease progression needs to be explored further. Further studies are needed to explore the varying presentation of vitiligo in individuals of all BMI subtypes and whether weight can help reduce the spread of the disease.
Abstract A006: The NALCN channel regulates metastasis and non-malignant cell dissemination
Authors: Eric Rahrmann, David Shorthouse, Amir Jassim, Linda Hu, Mariaestela Ortiz, Betania Mahler-Araujo, Peter Vogel, Marta Paez-Ribes, Atefeh Fatemi, Gregory Hannon, Radhika Iyer, Jay Blundon, Filipe Lourenço, Jonathan Kay, Rosaylnn Nazarian, Benjamin Hall, Stanislav Zakharenko, Douglas Winton, Liqin Zhu, Richard Gilbertson
Journal: Cancer Research (2023)

Abstract We identify the Sodium Leak Channel Non-Selective Protein (NALCN) as a key regulator of cancer metastasis and non-malignant cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric and colorectal cancers. Deletion of Nalcn from gastric (Prom1CreERT2/LacZ;KrasG12D;Trp53Flx/Flx; n=269), intestinal (Villin1-CreERT2;KrasG12D;Trp53Flx/Flx; n=141) or pancreatic adenocarcinomas (Pdx1-Cre;KrasG12D;Trp53Flx/+; n=55) in mice did not alter tumor incidence, but markedly increased the number of circulating tumor cells (CTCs) and metastases. Treatment of these mice (Villin1-CreERT2;KrasG12D;Trp53Flx/Flx; n=28) with gadolinium–an imaging contrast agent and NALCN channel blocker–similarly increased CTCs and metastasis. Deletion of Nalcn from mice that lacked oncogenic mutations and never developed cancer(Prom1CreERT2/LacZ; n=174), caused shedding of epithelial cells into the blood at levels equivalent to those seen in tumor-bearing animals. These cells trafficked to distant organs to form normal structures including lung epithelium and kidney glomeruli and tubules. Thus, NALCN regulates cell shedding from solid tissues independent of cancer, divorcing this process from tumorigenesis and unmasking a potential new target for anti-metastatic therapies. Citation Format: Eric Rahrmann, David Shorthouse, Amir Jassim, Linda Hu, Mariaestela Ortiz, Betania Mahler-Araujo, Peter Vogel, Marta Paez-Ribes, Atefeh Fatemi, Gregory Hannon, Radhika Iyer, Jay Blundon, Filipe Lourenço, Jonathan Kay, Rosaylnn Nazarian, Benjamin Hall, Stanislav Zakharenko, Douglas Winton, Liqin Zhu, Richard Gilbertson. The NALCN channel regulates metastasis and non-malignant cell dissemination [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A006.
Abstract B013: Tumor-derived CCL5 recruits’ cancer-associated fibroblasts and promotes tumor cell proliferation in esophageal carcinomas
Authors: Karen J. Dunbar, Qiaosi Tang, Tatiana A. Karakasheva, Anil K. Rustgi
Journal: Cancer Research (2023)

Abstract The tumor microenvironment (TME), at both the primary tumor and sites of metastases, is a key determinant in the success of metastatic colonization. Cancer-associated fibroblasts (CAFs) are a predominant cell type in the TME that, through deposition and remodeling of extracellular matrix (ECM) components, can mediate the TME and promote cancer progression. In addition to cancer progression and metastasis, CAFs have also been shown to mediate resistance to chemotherapy and radiotherapy. Therefore, there is a need to identify the factors which activate and recruit CAFs to solid tumors. Though cytokine arrays, we identified CC motif chemokine ligand 5 (CCL5) as a secreted factor which is increased upon co-culture of esophageal cancer cell lines and CAFs. Using CRISPR/Cas9 technology, we determined that CCL5 is predominantly tumor-cell derived and loss of tumor-cell derived CCL5 reduced esophageal carcinoma cell proliferation in vitro and in vivo. We propose that this reduction in cell proliferation is mediated by ERK1/2 signaling as loss of tumor-cell derived CCL5 reduces expression of p-ERK1/2 and cyclin D1, an ERK1/2 target gene which is essential for cell cycle progression. Interestingly, the loss of tumor-derived CCL5 also reduced the percentage of CAFs, identified by αSMA positivity, recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists called Maraviroc. We treated xenografts generated from esophageal carcinoma cell lines or patient derived tumor fragments with Maraviroc. Maraviroc treated xenografts had reduced tumor volume, CAF recruitment and ERK1/2 signaling. Thus, mimicking the effects of the genetic loss of CCL5. Analysis of the TCGA database, identified that high CCL5 or CCR5 expression is associated with poorer prognosis in low grade esophageal carcinomas. Together, we propose that this data highlights the importance of CCL5 in esophageal carcinomas with regards to CAF recruitment and tumor cell proliferation, and that the maraviroc in vivo experiments suggest that targeting the CCL5-CCR5 axis may have therapeutic potential in esophageal carcinomas. Citation Format: Karen J. Dunbar, Qiaosi Tang, Tatiana A. Karakasheva, Anil K. Rustgi. Tumor-derived CCL5 recruits’ cancer-associated fibroblasts and promotes tumor cell proliferation in esophageal carcinomas [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B013.
Abstract IA026: Chromosomal instability as a driver of cancer metastasis
Authors: Samuel F. Bakhoum
Journal: Cancer Research (2023)

Abstract Chromosomal instability (CIN) is a hallmark of human cancer that is associated with metastasis and immune evasion. Yet, how CIN shapes the tumor microenvironment (TME) to facilitate tumor progression remains poorly understood. We undertook a systems level approach to better define the impact of CIN on cancer cell states as well as TME phenotypes and found that cancer cell CIN engenders a pro-metastatic TME that is markedly enriched for immune-suppressive macrophages, a granulocytic infiltrate, and dysfunctional T cells. We then developed a novel computational tool to infer conditionally dependent cell-cell interactions from single cell RNA sequence data to define tumor-derived factors that shape the TME and promote metastatic dissemination. This work led to the identification of novel therapeutic targets in chromosomally unstable tumors and sheds light on key mechanisms by which CIN cooperates with the immune system to drive disease progression. Citation Format: Samuel F. Bakhoum. Chromosomal instability as a driver of cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA026.
Abstract IA009: Biology and vulnerabilities of circulating tumor cell clusters
Authors: Nicola Aceto
Journal: Cancer Research (2023)

Abstract The metastatic spread of cancer occurs through the generation and hematogenous dissemination of circulating tumor cells (CTCs). Among these, CTC clusters have recently emerged as key players in the metastatic process. With a combination of microfluidic technologies and single cell-resolution molecular analysis applied to cancer patients and mouse models, we gained fundamental insights into the biology, vulnerabilities, and clinical implications of CTC clusters. For instance, we found that their physical features enable molecular changes that promote stemness and metastasis, allowing us to define new treatment concepts aimed at suppressing their metastatic potential. Further, we investigated CTC heterogeneity at the single cell level, revealing fundamental interactions that occur between CTCs and immune cells and that accelerate metastasis formation, as well as microenvironment signals that impact on CTC generation. More recently, we also gained important insights into CTC generation dynamics and signals that trigger intravasation. Together, our findings support a model whereby upon defined microenvironmental cues, CTCs form multicellular aggregates to expand their metastatic ability, providing a new rationale for targeting these interactions in cancer. Citation Format: Nicola Aceto. Biology and vulnerabilities of circulating tumor cell clusters [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA009.